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Diabetes:抑制基质金属蛋白酶9活性降低细胞炎症

来源:生物谷 2012-07-24 22:15

绝大多数Ⅰ型糖尿病、无胰岛素抗体和低水平C肽Ⅱ型糖尿病,糖尿病肾病,器官移植后糖尿病,胰腺疾病或胰腺切除导致的糖尿病等4类患者,适合进行成人胰岛细胞移植。胰岛腺移植作为1型糖尿病根治手段之一,近年来也取得了许多进展。

然而,移植后的胰岛细胞会遭到破坏,以及产生炎症反应。基质金属蛋白酶(MMP)-2和-9虽然参与细胞外基质的重塑和白细胞的迁移,但其对移植的胰岛细胞的作用却尚未明了。

近日,发表在Diabetes杂志上的一项研究对比了对照组和移植胰岛后小鼠体内的MMP-2 mRNA表达水平,发现MMP-2 mRNA变化差异不明显,而MMP-9 mRNA和蛋白表达水平在移植胰岛的小鼠体内明显增高。

MMP-9敲除的小鼠体内白细胞表达的CD11b(MAC-1)和中性粒细胞的Ly6G免疫组化结果显示胰岛移植到肝脏后,炎性细胞的迁移大幅减少。

此外,抑制明胶酶能减少巨噬细胞和中性粒细胞的大量迁移,抑制炎症反应的发生,同时也提高移植的胰岛细胞成功的数量。

这些结果表明,活性胰岛细胞移植后MMP-9表达会增加,该蛋白表达的升高直接增强白细胞的迁移,因此要想早期胰岛移植后胰岛细胞的存活后就要抑制基质金属蛋白酶9来实现。(生物谷:Bioon.com)

Inhibition of Gelatinase B (Matrix Metalloprotease-9) Activity Reduces Cellular Inflammation and Restores Function of Transplanted Pancreatic Islets

Neelam Lingwal, Manju Padmasekar, Balaji Samikannu, Reinhard G. Bretzel, Klaus T. Preissner and Thomas Linn

Islet transplantation provides an approach to compensate for loss of insulin-producing cells in patients with type 1 diabetes. However, the intraportal route of transplantation is associated with instant inflammatory reactions to the graft and subsequent islet destruction as well. Although matrix metalloprotease (MMP)-2 and -9 are involved in both remodeling of extracellular matrix and leukocyte migration, their influence on the outcome of islet transplantation has not been characterized. We observed comparable MMP-2 mRNA expressions in control and transplanted groups of mice, whereas MMP-9 mRNA and protein expression levels increased after islet transplantation. Immunostaining for CD11b (Mac-1)-expressing leukocytes (macrophage, neutrophils) and Ly6G (neutrophils) revealed substantially reduced inflammatory cell migration into islet-transplanted liver in MMP-9 knockout recipients. Moreover, gelatinase inhibition resulted in a significant increase in the insulin content of transplanted pancreatic islets and reduced macrophage and neutrophil influx compared with the control group. These results indicate that the increase of MMP-9 expression and activity after islet transplantation is directly related to enhanced leukocyte migration and that early islet graft survival can be improved by inhibiting MMP-9 (gelatinase B) activity.

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